Flashcards
Renal Disease
Cards in this deck (102)
- 1classifications of renal failureacute renal failure (ARF)
chronic renal failure (CRF / CKD) - 2acute renal failure (ARF)rapid onset, potentially reversible cause
Pre - renal ARF (anything causing renal hypoperfusion)
Intrinsic ARF (anything causing direct intrinsic renal damage)
Post-renal ARF (anything causing obstruction - eg kidney stone) - 3chronic renal failure (CRF / CKD)develops over months to years; continuum from GFR 90mL/min to ESRD
everyone will have age related decline in renal function. CRF is unrelated to age linked decline
Eventually leads to ESRD requiring intervention to sustain life - 4Dx Renal DiseaseHistory
urinalysis, microscopy
renal imaging
renal function tests (SrCr, Urea, GFR) - 5assessment of renal function - GFRInulin clearance is the gold standard test
serum creatinine - 6MDRD Equation for GFR EstimateOriginal Formula (6 variables!)
GFR(ml/min)=
170 x SeCr-0.999 x Age-0.176 x Urea-0.170 x Albumin 0.318 x (0.762iffemale) x (1.180 Af.American)
Abbreviated MDRD (Reported on laboratory results)
GFR (ml/min/1.73m2) =
186 x (SeCr/88.4)-1.154 x Age-0.203 x (0.742 if female) x (1.212 if Af. American)
Need to correct for Body Surface Area for patients real GFR
BSA = (Weight (kg))0.425 x (Height (cm))0.725 x 0.007184 - 7treatment ESRDperitoneal dialysis
haemodialysis
transplant - 8Haemodialysisdiffusion and ultrafiltration remove solutes and H2O across a semi permeable membrane
dialysis fluid is composed of Na+, K+, Ca+, Mg+, Cl-, bicarbonate, lactate, and acetate
haemodyalysis is unphysiologic - large rapid volume and solute shifts - 9principles of haemodialysisdialysis alters the solute composition of a patient's blood by exposing it to dialysate
water and other LMW compounds pass through the pores in membranes either by:
diffusion or ultrafiltration/convection - 10diffusion in haeodialysisResults from random molecular motion and depends on frequency of contact of molecule with membrane. This is enhanced by a concentration gradient and limited by size of molecule.
- 11Ultrafiltration/convection in haemodialysisWater is driven across the membrane by a hydrostatic or osmotic force across the membrane, and thus “dragging” solutes with it (limited by size).
- 12vascular access for haemodialysistemporary vascath- internal jugular, subclavian, femoral vein: acute situations, not good long term due to complications
semi-permanent permcath- useful bridging to permanent access, or in cases of no options; reduces infection risk
permanent AV fistula- best long term option, need 6-8 weeks maturation - usually on forearm - 13types of dialysisintermittent vs continuous
- 14peritoneal dialysisrequires permanent catheter in the peritoneal cavity
2L dialysis 4 times a day
smoother metabolic control and BP
complications include infective peritonitis (mostly gram positive from skin) and requiring higher anti hyperglycaemic requirements due to the glucose load - 15ceasing dialysispotassium builds up and causes cardiac arrest
hypervolaemia
dead - 16nephrotic syndromeclinical state characterised by proteinuria and hypoalbuminaemia
hyperlipidaemia
oedema
hypertension
from a variety of causes due to increased permeability of the glomerular basement membrane
- glomerulonephritis
- diabetic neuropathy
- amyloid infiltration
- lupus
- drugs - 17primary causes of ESRDglomerulonephritis
diabetic neuropathy - 18glomerulonephritisinflammation of the glomeruli
integrity of membrane is compromised damage and infiltration for WBCs
antibody mediated injury
glomerulus becomes inflamed, leading to the membrane becoming leaky- lose protein - 19treating glomerulonephritisif immune related: immunosuppressive therapy
- prednisolone (up to 100mg daily) [use bisphosphonates and PPI]
- cyclophosphamide oral or IV
- chlorambucil
- cyclosporin
- azathioprine
- mycophenolate
antiproteinuric therapy
- ACEI or A2RA therapy
+ antihypertensive therapy
CCB / beta blockers
diuretic therapy for oedema
antibacterial prophylaxis (Trimethoprim/sulfamethoxazole) - 20hypertension in CRFa cause and symptom of renal failure
as RF progresses the individual nephrons compensate to maintain GFR, leading to intraglomerular hypertension and causes direct endothelial damage
BP control helps improve outcome and progression of disease - target 130/80
blocking renin angiotensin system beneficial - 21glycemic control in CRFtight control reduces risk of diabetic neuropathy
reduces progression from albuminuria to neuropathy
glycemic control is important at all stages of kidney disease
once overt neuropathy occurs, benefit lessens, and no signs of benefit in stage 5 kidney disease - 22hypoglycaemic agents and kidney diseaseInsulin- metabolism partially dependent on renal function; as renal function decreases, insulin clearance becomes variable and unpredictable
Metformin is extensively renally cleared - in severe impairment, can result in metabolic acidosis -not recommended GFR <60mL/min, and CI <30mL/min
Sulphonylureas - Gliclazide recommended as shorter t1/2 and no active metabolites - dose can be similar to those with typical function - 23antihypertension therapy in kidney diseaseACEIs and A2RBs, BBs and diuretics work well - may need multiple agents. protective, antiproteinuric effect.
CCBs have less of the antiproteinuric effect than the above; seen primarily with diltiazem and verapamil (the non dihydropyridines) vs dihydropyridines - 24proteinuria and disease progressionproteinuria contributes to disease progression - mesangial toxicity, tubular overload, toxicity from filtered compounds, induction of pro-inflammatory cytokines
-->
blockade of RAS - reduces tubular damage by reducing tubular exposure to protein, lower systemic blood pressure, lower glomerular capillary pressure and improve permeability , inhibit hypertrophy - 25the ACEI / A2RI paradoxbrief dip in renal function upon commencement, but long term protection slowing disease progression over time
- 26polycystic kidney diseaseinherited disease, cysts form over kidneys, distorting architecture of the kidney, disrupting function, activating RAS, and causing pain. Cysts may rupture and become infected.
- 27kidney stones (nephrolithiasis)Variable presentation from asymptomatic through to intense pain, haematuria, infection, oliguria and uraemia
mostly made of calcium, some uric acid and cystine
treatment: increased fluid intake, modification of urinary pH, surgery - 28signs and symptoms of CRF and Uraemiagenerally asymptomatic until GFR <15mL/min
symptoms due to accumulation of 'uraemic' toxins, such as urea, oxalates, phosphates and protein bound molecules
symptoms:
N&V
anaemia (lethargy)
malnutrition (anorexia, acidosis)
Uraemic pericarditis
dyspnoea (pulmonary oedema)
bone pain, gout
poor concentration
uraemic encephalopathy
fits, coma
burning, pain in extremities
tremor - 29renal anaemiareduced EPO production from kidney
iron deficiency
b12 + folate deficiency (dialysis)
hyperparathyroidism
aluminium toxicity
chronic infection and inflammation
bone marrow failure
malignancy
RBC fragility
acute and chronic blood loss
haemolytic anaemia - 30effects of anaemiaChronic tiredness and lethargy
• Reduced exercise tolerance
• Shortness of breath
• Reduced cognition and concentration
• Reduced libido
• Reduced immune responsiveness
• Increased cardiac output and Left ventricular hypertrophy
• Pale skin and mucous membranes - 31managing renal anaemiaAddress other causes first
• Erythropoietin (ESAs)
• Iron
• Vitamins B, C & Folate
• Transfusion
only partially correct
correct to 100-120g/L . do not over correct to “normal” this is detrimental in regards to CV risk - 32Erythropoietin Therapynot for emergency situations
Require frequent monitoring of Hb, Iron vitamin B12/ folate status, Hb
– During correction phase, check Hb every 2-4 weeks and iron stores every month
– During maintenance phase, check Hb every month and iron stores every 3 months - 33iron therapy in CKDiron deficiency is the most common cause of EPO treatment failure in CKD, so iron studies are important.
transferrin indicates functional iron deficiency while ferritin indicates absolute iron deficiency
IV iron is preferred as oral is poorly absorbed, has low potency and ineffective in haemodialysis
intermittent vs continuous - no overall difference in outcome - 34vitamin supplementation in CKDCKD anorexia and dietary restrictions can result in malnutrition
supplement with vitamin C (ascorbic acid)
folic acid
mega B - 35blood transfusions in CKDreserved for emergency, as can predispose them to developing antibodies, making organ transplant more complicated
Immunosuppression cover of transfusions
– Cyclosporin (4mg/kg bd 6 doses)
– Azathioprine
– Mycophenolate
Ensure transplantable patients are covered - 36CKD mineral and bone disorderrenal osteopathy
extra-skeletal calcification
parathyroid hyperplasia and disrupted phosphate, parathyroid hormone, calcium and vitamin D metabolism - 37parathyroid gland hyperplasiaglands grow in size, become nodular hyperplasic, and cells proliferate aggressively
decreased sensitivity to calcium and vitamin d
chronic PTH over secretion
refractory to medical treatment - 38renal osteodystrophyexcess calcium or vitamin d and dysfunctional parathyroid gland, leads to mixed lesions
kidney washes phosphate out of blood. in renal failure, it accumulates , has negative effect on vitamin D production and calcium levels. . parathyroid released, takes calcium out of bones. (renal osteodystrophy) - 39extra skeletal calcificationhigh phosphate levels - smooth muscle cells differentiate and turn into bone forming cells; high phosphate levels can calcify smooth muscle tissue (including blood vessels) affects heart etc
soft tissue arterioles can become calcified, and this affects the skin - 40treating CKD mineral and bone disordercontrol serum phosphate <1.6mmol/L
- dialysis
- restrict dietary phosphate
- phosphate binders with meals
Vitamin D analogues (calcitriol/paracalcitriol)
- reduces PTH levels
- increases calcium absorption to bone
maintain calcium levels to suppress PTH
calcimimetics -
(cinacalcet in dialysis patients only) - 41controlling phosphorusdiet control
dialysis
phosphate binders - 42metalic ion phosphate binderscalcium carbonate
aluminium based binders
sevelamer (synthetic non-ionic)
lanthanum carbonate
sucroferric oxyhydroxide
vitamin D sterols - 43metalic ion phosphate binders: calcium carbonatefist line intermediate phosphate binder
can over suppress PTH and cause adynamic bone disease
risk of hypercalcaemia, especially if given with vitamin D - 44metalic ion phosphate binders: aluminium based binderpotent binder
associated with cognitive disturbances (dementia)
bone disease
anaemia - 45metalic ion phosphate binders: sevelamerfirst synthetic phosphate binder
reduces serum phosphate
reduces serum calcium
as effective as calcium carbonate
reduction in calcium (small but signifiant)
metabolic disturbances
N&D - 46metalic ion phosphate binders: lanthanum carbonatehigh potency binder
chewable chalky tablets
bound to proteins, only .0013% absorbed
excreted in bile - 47metalic ion phosphate binders: sucroferric oxyhydroxidevelphoro
chewable tablet take 3 times daily
low iron uptake - 48metalic ion phosphate binders: vitamin D sterolsincrease intestinal calcium absorption
contributes to calcium hypercalcaemia
but low vitamin D reduces GI calcium absorption and can lead to PTH increase
increases intestinal phosphate absorption
increases bone mineralisation
inhibits synthesis of PTH
low vit D triggers PTH production
too much may over suppress PTH
regulates calcium and phosphate - 49calcimimeticscinacalcet
allosteric activation
dialysis patients only - 50parathyroidectomytotal parathyroidectomy and forearm autograft
subtotal parathyroidectomy
removal of part of the gland
calcium monitoring post op
need huge doses of calcium initially - 51calciphylaixis treatment (calcific uremic arteriolopathy (CUA), is a rare painful syndrome of calcification of the small blood vessels located within the fatty tissue and deeper layers of the skin,)reduce levels of procalcifying factors
- avoid vitamin D and calcium supplements
use calcium free phosphate binders
- increase frequency of haemodialysis
switch from peritoneal to haemodialysis
use low calcium in dialysis
-bisphosphonates
-Cinacalcet in hyperparathyroidism (dialysis patients only)
- stop vitamin k agonists (warfarin; stops the body protecting itself from calcification) - 52hyperkalaemia in CKD/CRFhyperkalaemia causes arrhythmia and an be fatal
hyperkalaemia is caused by decreased K+ excretion due to renal impairment
treat if >6.0 - 53treating hyperkalaemia in CKD/CRFdepends on severity:
- control K intake from diet
- modify drugs increasing K levels (eg ACEI/A2RI, spironolactone)
- use potassium binding resins (resonium)
- IV insulin and dextrose (acute treatment)
- salbutamol (shifts K inside cells)
- correct acidosis (bicarb)
- calcium carbonate to stabilise cardiac membrane, caution digoxin
-dialysis (WITHOUT POTASSIUM! DO YOU WANT TO KILL A MOFO? NO - BE CAREFUL!) - 54acid / base imbalancethe kidneys normally generate bicarbonate to keep pH levels stable. obvs disrupted in CRF
-> acidic conditions
give bicarb capsules
can often be stopped once dialysis starts - 55bleeding and anti-coagulation issuesCRF increases bleeding risks
- uraemia affects platelet function
caution LMWH as it accumulates in renal impairment
warfarin and heparin dosed as normal but monitor APTT and INR - 56Gout and Hyperuricemiauric acid accumulation is common in renal impairment - leads to gouty attacks and uric acid stone formation
treat - allopurinol, consider reducing dose
caution colchicine (dehydration risk if diarrhoea occurs)
avoid NSAIDs (duh) consider steroids - 57restless leg syndromecommon complication
give:
benzo (clonazepam 0.5mg nocte)
levodopa/carbidopa
praimpexole - 58oedema / fluid overloadreduced renal function = reduced urine output
low albumin in nephrotic syndrome (leaky vessels)
LOOP DIURETICS - mega doses as low doses are ineffective in renal failure - 59GI problemspatients with advanced CRF usually have GI issues; anorexia, N&V, constipation
dialysis helps these issues
give PPI, caution antacid
treat constipation - 60renal transplantusually the shitty kidney is left behind and the new kidney is attached somewhere nearby
try and match as close as possible, but even an exact HLA match still requires the drugs - 61principles of immunosuppressant therapy in renal transplantpersonalised therapy based on risk of organ rejection
hit hard initially, reduce to minimal effective dose
manage risks of immunosuppression
ensure ongoing monitoring - patients take these drugs forever - 62standard drug regimen in transplant
- 63calcineurin inhibitorsprevents production of interleukin‑2 and other cytokines, which normally stimulate T cell proliferation and differentiation, by forming complexes with cytoplasmic immunophilins (cyclophilin and FKBP‑12 respectively), which block the action of calcineurin in activated T cells.
Tacrolimus used more often than cyclosporin as more potent and less cosmetic side effects - 64azathioprine in transplantanti proliferative effects
- 65mycophenolic acid in transplantinhibits immune cells - particularly B Cell- needs it’s DNA replication. IMPH helps generate building blocks. Myclophenoic acid blocks IMDPH so it can’t copy it’s DNA and stops replicating
- 66BasiliximabChimeric monoclonal antibody against interleukin‑2 receptors expressed on activated human T lymphocytes; blocks binding of interleukin‑2, inhibiting T lymphocyte proliferation.
- 67mTOR inhibitorsBind to the same intracellular protein (FKBP‑12) as tacrolimus; however, the protein-drug complex blocks the activity of mTOR kinase, preventing cell cycle progression and cytokine-induced T and B cell proliferation
- 68Sirolimus (Rappamune®) Everolimus (Certican®)mTOR inhibitors;
Can potentiate CNI nephrotoxicity
– Use in Long term maintenance
• Calcineurin avoidance
• Long term patients with calcineurin nephrotoxicity (CAN)
less increase in BP (advantage over calcineurin inhibitors) - 69treating acute organ rejectionmethylprednisolone
polyclonal antibodies
thymoglobuline - 70methylprednisolone in acute organ rejectionSteroids reverse rejection by killing Lymphocytes involved in rejection
1g IV daily, for 3 days - 71polyclonal antibodies in acute organ rejectiondeplete T cells, mask T antigens and prevent T cell proliferation
- 72thymoglobuline in acute organ rejectionsmashes up T cells
- 73Highly Sensitized Patientshave been exposed to foreign MHC, primed for rejection
previous transplant, pregnancy, blood transfusion etc
desensitise - rapture protocol - 74rapture desensitisation protocolrituximab (destroys B cells)
mycophenolate (suppresses lymphocyte proliferation and antibody formation) - 75side effects of immune suppressioninfections and malignancy
mTOR inhibitors delay wound healing; so not great immediately after surgery
if further surgery required, would have to cease and swap to alt drug
prevent infections
Avoid close contact with infected people
• Wash hands after toilet, touching pets and before eating
• Seek medical advice ASAP if suspect infection - 76chronic CNI toxicityRenal calcineurin inhibitor (CNI) toxicity is a frequent side effect of immunosuppression with CNIs in solid organ transplantation, leading to acute and chronic renal failure.
Treat by reduction or withdrawal of CNIs
– Traditionally difficult
– Non-CNIs (MMF/SRL/ERL) potentially
allow safe dose reduction - 77acute CNI nephrotoxicity
- 78immunosuppressant drug interactions (some have a 10x fold increase in concentration - be cautious!)
- 79immunosuppressant TDMMost immunosuppressants fit the criteria of a good TDM drug
– Relationship between concentration and effect/toxicity
– Narrow Therapeutic Index
– Wide inter and intra patient pharmacokinetic variability
– Poor relationship between dose & blood concentration (low bioavailability)
– Potential for drug interactions with other medications (CYP3A/Pgp)
– Assess compliance - 80tacrolimus TDMC0 trough used
good correlation with AUC
targets:
8-12ng/mL for 30 days after transplant
4-8ng/mL thereafter - 81siroliums TDMC0 used
target depends on if sole agent or with anti proliferative - 82Mycophenolate TDMBenefits of TDM less well established
• Useful in confirming clinical events
– Rejection or Toxicity
• Trough Levels have primarily been used
– 1.5-3.5mcg/mL
• Evidence and trials supporting multipoint AUC may be better
– 0,1,3,6hAUC
– AUC>44mcg/ml.h - 83timing of transplant medicationsClinical practice
– Convenient to group medications twice a day ≅ 12-hour intervals
– Ignore recommendations as long as *consistency* is achieved, particularly around food, as food affects absorption of many of these drugs
ALSO DO NOT CHANGE BRANDS ONCE COMMENCED ON A BRAND! - 84other drugs used in renal transplantationanti-infective prophylaxis (anti-fungal, anti-viral, anti-bacterial)
acid suppression (PPI)
anti-hypertensive
cholesterol (especially patients on mTOR inhibitors, sirolimus and everolimus) - 85Cytomegalovirus Disease (CMV) in CRFrisk in organ transplant - prophylaxis with Valganciclovir Hydrochloride
- 86Effect of Renal Impairment on Drug Pharmacokinetics (ADME)Absorption: affected by NVD, reduced gastric emptying, phosphate binders
Distribution: changes in fluid states - where fluid is in the body and how much of it there is (Vd) and amount of albumin (protein binding)
Metabolism: primarily hepatic function so don’t expect this to be greatly effected but Uraemia can alter liver function (increased or decreased metabolism)
Excretion: reduction in renal excretion most significant and these are the cases that usually warrant dose reduction - 87considerations in dosingrenal function - good, poor, dialysis?
stable or fluctuating?
how is the drug cleared?
does the drug have active metabolites that are cleared by kidney? - 88should we avoid nephrotoxic drugswell yeah, if possible
risks: direct toxins (aminogyclosides, calcinuerin inhibitors, lithium)
obstructive uropathy (antivirals, statin induced myopathy)
NSAIDs - 89consider drugs aggravating metabolic and physiological effects of renal impairmentHyperkalaemia
* ACEIs, A2RIs, K sparing diuretics, eplerenone
Cataboilc effects of uraemia
drugs causing sodium retention
drugs causing fluid retention
*CCBs, glitazones
Drugs causing anaemia - 90watch out for IVs and dugs requiring a lot of fluid to consume (bisphosphonates)fluid restrictions etc
- 91Changing Drug Doses in Renal Impairment• “Dose” Method
– Dosing interval kept constant and size of dose is reduced
• “Interval” Method
– Dose size is kept constant and dose interval is increased
• “Combination” Method
– Dose size is reduced and dose interval is increased - 92Changing Drug Doses in Renal Impairment gentamicin• “Concentration dependant” anti-bactericidal activity – Fe≈95%
• “Oto” and “Nephro” Toxicity when it accumulates
• Total daily dose reduced but
– Size of each dose should remain the same – Dose interval increased
- 93Changing Drug Doses in Renal Impairment vancomycin“Time Above MIC” dependant Antibactericidal activity
• Fe ≈ 100%
• Toxicity when it accumulates
• Either smaller or less frequent doses can be given and blood concentrations can
be used to time next doses
• Dosing can occur every 5 days or more in ESRD patients
- 94Dose Changes in Renal Failure • Loading DosesLoading Doses
– Rarely changed in Renal Impairment – Uraemia can sometimesinfluence Vd
Dloading = Vdistribution x Css desired - 95Dose Changes in Renal Failure maintenance doseMaintenance Doses
– Need to be modified
– How much to reduce?
– Assume
• No change in bioav ailability, Vd and non-renal clearance
• Proportional reduction in dose according to reduction in GFR
• Estimate and round of f!
(D/T)(RI) = 1 - Fe [ 1 - Fraction of Remaining Function] (D/T)(Norm)
- 96Factors Affecting Dialysis Drug Clearancedrugs that are extensively protein bound will remain bound on dialysis, drugs in tissue likewise- only free drug in plasma dialysed
MWt <500Da are removed efficiently by Haemodialysis
– Large molecules cleared better by Hemofiltration
water soluble drugs removal improved by ultrafiltration - 97dosing regimensChanges in the dosing schedule need to be practical and easy to follow
- 98pain relief in CKD/CRF/transplantNSAIDs
– Avoid in CRF patients (worsen impairment)
– May be acceptable in ESRD!
Opioids
– Avoid Morphine (Active Metabolite)
– Avoid Pethidine (Toxic Metabolite)
– Fentanyl & Oxycodone preferred
• Low dose TCAs – Dose as normal
• Gabapentin/Pregabalin
– Neuropathic Pain
– Dose reductions essential - renally cleared - 99diureticsAvoid Thiazides for diuretic effect
– Don’t work as well at low GFR but still reduce blood pressure
Avoid Potassium Sparing Diuretics – Don’t work as well at low GFR and a major cause of hyperkalaemia
Furosemide preferred, use big doses (250-500mg twice a day) - 100cholesterol lowering therapynormal dose of statins
– Reduce the dose of fenofibrate in severe renal impairment - 101smoking cessationNRT safe in renal impairment
Varenacline (Champix) - renally cleared; dose reduction and cautious titration required - 102anti infectivecaution:
aminolycosides
carbapenems
fluroquinolones
benpen
sulphonamides
fluconazole
antivirals (aciclovir, famciclovir, valaciclovir - can accumulate and cause nephrotoxicity)
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- Advanced Therapeutics Flashcards on Renal Disease, created by Amelia Claire on 12/03/2019.
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- Amelia Claire · Mar 2019
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- Mar 19, 2019
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